DESCRIPTION: The search for an "AIDS cure" has led to the discovery of many non-nucleoside inhibitors of the AIDS virus. Several non-nucleoside inhibitors are being intensely pursued since drug combinations of non-nucleoside and protease inhibitors offers a promising therapy for preventing rapid mutation of the AIDS virus. Numerous non-nucleoside inhibitors have recently been isolated from natural sources and suggest an intriguing relationship between HIV reverse transcriptase inhibition and a common structural and functional unit. The minimum structural and functional unit is embodied in the marasmane-based sesquiterpenoids, a class of natural products containing several potent reverse transcriptase inhibitors. A general route to this core unit is described that will lead to the syntheses of marasmene (the parent marasmane natural product), kuehneromycin A (a more highly functionalized marasmane), and several analogs containing the putative functionality responsible for reverse transcriptase inhibition. The proposal describes a general synthesis of marasmane-type metabolites that both exploits and expands the fundamental reactions of alpha-cyanocyclohexenones. Preliminary results demonstrate the unique reactivity of alpha-cyano cyclocyclohexenones that will allow two previous limitations of the nitrile group to be overcome; diastereoselective conjugate additions to unsaturated nitriles and stereoselective cyclization reactions. The three specific aims of this proposal are: (1) Diastereoselective conjugate additions with hydroxylated alpha-cyanocyclohexenones. (2) Stereoselective cyclization of nitrile anions to cis- and trans-decalins. (3) The asymmetric synthesis of marasmene, kuehneromycin A, and related anti-HIV analogs. This proposal describes research of general use in determining the structural and functional requirements for marasmane-based reverse transcriptase inhibitors while expanding the reactions of nitriles.